4MY6

EnaH-EVH1 in complex with peptidomimetic low-molecular weight inhibitor Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-OH

Summary for 4MY6

• Entry DOI: 10.2210/pdb4my6/pdb
• Related PRD ID: PRD_001198
• Descriptor: Protein enabled homolog, (3aR,5aS,8S,10aS)-1-[(3S,6R,8aS)-1'-[(2S)-2-acetamido-3-(2-chlorophenyl)propanoyl]-5-oxidanylidene-spiro[1,2,3,8a-tetrahydroindolizine-6,2'-pyrrolidine]-3-yl]carbonyl-10-oxidanylidene-2,3,3a,5a,8,10a-hexahydrodipyrrolo[3,2-b:3',1'-f]azepine-8-carboxylic acid, BROMIDE ION, ... (4 entities in total)
• Functional Keywords: molecular recognition, actin dynamics, cell adhesion-inhibitor complex, cell adhesion/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q8N8S7
• Total number of polymer chains: 2
• Total formula weight: 26768.67

Authors

Barone, M.,Roske, Y.,Kuehne, R. (deposition date: 2013-09-27, release date: 2014-10-15, Last modification date: 2023-09-20)

Primary citation

Opitz, R.,Muller, M.,Reuter, C.,Barone, M.,Soicke, A.,Roske, Y.,Piotukh, K.,Huy, P.,Beerbaum, M.,Wiesner, B.,Beyermann, M.,Schmieder, P.,Freund, C.,Volkmer, R.,Oschkinat, H.,Schmalz, H.G.,Kuhne, R.
A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions.
Proc.Natl.Acad.Sci.USA, 112:5011-5016, 2015

PubMed Abstract: Small-molecule competitors of protein-protein interactions are urgently needed for functional analysis of large-scale genomics and proteomics data. Particularly abundant, yet so far undruggable, targets include domains specialized in recognizing proline-rich segments, including Src-homology 3 (SH3), WW, GYF, and Drosophila enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Here, we present a modular strategy to obtain an extendable toolkit of chemical fragments (ProMs) designed to replace pairs of conserved prolines in recognition motifs. As proof-of-principle, we developed a small, selective, peptidomimetic inhibitor of Ena/VASP EVH1 domain interactions. Highly invasive MDA MB 231 breast-cancer cells treated with this ligand showed displacement of VASP from focal adhesions, as well as from the front of lamellipodia, and strongly reduced cell invasion. General applicability of our strategy is illustrated by the design of an ErbB4-derived ligand containing two ProM-1 fragments, targeting the yes-associated protein 1 (YAP1)-WW domain with a fivefold higher affinity.

PubMed: 25848013
DOI: 10.1073/pnas.1422054112

Experimental method

X-RAY DIFFRACTION (1.7 Å)